Examining the roles of cannabinoids in pain and other therapeutic indications: a review

Importance of the field: In recent times, our knowledge of cannabinoids and the endocannabinoid system has greatly advanced. With expanding knowledge, synthetic cannabinoids – including nabilone, dronabinol and a combination of synthetic Δ9-THC and cannabidiol – have been developed and tested for benefit in a variety of therapeutic indications.

Areas covered in this review: The aim of this article is to provide a summative review of the vast amount of clinical trial data now available on these agents.

What the reader will gain: To locate clinical trials for review, a literature search was performed using PubMed between the dates of 25 May and 30 June 2009. Search parameters were set to isolate only human randomized controlled trials (RCTs) published between 1990 and 2009. Keywords consistently used for each search include: cannabinoids, marijuana, THC, nabilone and dronabinol. Preferential selection was given to the best-designed trials, focusing on placebo-controlled, double-blind RCTs with the largest patient populations, if available.

Take home message: As efficacy and tolerability of these agents remain questionable, it is important that cannabinoids not be considered ‘first-line’ therapies for conditions for which there are more supported and better-tolerated agents. Instead, these agents could be considered in a situation of treatment failure with standard therapies or as adjunctive agents where appropriate.     

Δ-Tetrahydrocannabivarin testing may not have the sensitivity to detect marijuana use among individuals ingesting dronabinol

The purpose of this study was to determine whether Δ⁹-tetrahydrocannabivarin (THCV), a plant cannabinoid, is a sensitive measure to detect recent marijuana use in cannabis dependent patients. It has been purported that smoking an illicit plant cannabis product will result in a positive THCV urinalysis, whereas the oral ingestion of therapeutic THC such as dronabinol will result in a negative THCV urinalysis, allowing for discrimination between pharmaceutical THC products and illicit marijuana products. In a double-blind placebo-controlled trial to determine the efficacy of dronabinol in cannabis dependence, all 117 patients produced a positive urine for the marijuana metabolite 11-nor-Δ⁹-THC-9-carboxylic acid; THC-COOH, but 50% had an undetectable (<1 ng/ml) THCV-COOH test. This suggests that THCV may not be a sensitive enough measure to detect recent marijuana use in all heavy marijuana users or that its absence may not discriminate between illicit marijuana use and oral ingestion of THC products such as dronabinol. We propose that the lack of THCV detection may be due to the variability of available cannabis strains smoked by marijuana users in community settings.     

Delta‐9-THC based monotherapy in fibromyalgia patients on experimentally induced pain,axon reflex flare,and pain relief

ABSTRACT

Objective: Fibromyalgia (FM) is a chronic pain syndrome characterized by a distinct mechanical hyperalgesia and chronic pain. Recently, cannabinoids have been demonstrated as providing anti-nociceptive and anti-hyperalgesic effects in animal and human studies. Here, we explored in nine FM patients the efficacy of orally administered delta-9-tetrahydrocannabinol (THC) on electrically induced pain, axon reflex flare, and psychometric variables.

Research design and methods: Patients received a daily dose of 2.5–15?mg of delta‐9-THC, with a weekly increase of 2.5?mg, as long as no side effects were reported. Psychometric variables were assessed each week by means of the West Haven-Yale Multidimensional Pain Inventory (MPI), Pittsburgh Sleep Quality Index (PSQI), Medical outcome survey-short form (MOS SF‐36), the Pain Disability Index (PDI), and the Fibromyalgia Impact Questionnaire (FIQ). In addition, patients recorded daily, in a diary, their overall pain intensity on a numeric scale. Each week, pain and axon reflex flare was evoked experimentally by administration of high intensity constant current pulses (1?Hz, pulse width 0.2?ms, current increase stepwise from 2.5–12.5?mA every 3 minutes) delivered via small surface electrodes, attached to the volar forearm skin.

Main outcome measures: Daily pain recordings by the patient, experimentally induced pain, and axon reflex flare recorded by a laser Doppler scanner.

Results: Five of nine FM patients withdrew during the study due to adverse side effects. Delta‐9-THC had no effect on the axon reflex flare, whereas electrically induced pain was significantly attenuated after doses of 10–15?mg delta‐9-THC (?p < 0.05). Daily-recorded pain of the FM patients was significantly reduced (?p < 0.01).

Conclusions: This pilot study demonstrated that a generalized statement that delta‐9-THC is an analgetic drug cannot be made. However, a sub-population of FM patients reported significant benefit from the delta‐9-THC monotherapy. The unaffected electrically induced axon reflex flare, but decreased pain perception, suggests a central mode of action of the cannabinoid.     

Ketamine for the treatment of chronic non-cancer pain

Importance of the field: Worldwide the number of patients affected by chronic pain is growing and conventional treatment is often insufficient. Recently the importance of the N-methyl-d-aspartate receptor (NMDAR) in the mechanisms and maintenance of chronic pain was established. Ketamine (introduced in the 1960s as an anesthetic) is the most studied NMDAR antagonist in the treatment of various chronic pain syndromes.

Areas covered in this review: The pharmacology, safety and toxicology of ketamine are discussed. Further, electronic databases were scanned for prospective, randomized controlled trials that assessed ketamine's analgesic effect in patients with chronic pain. The focus of this review is on trials published after 2008 that applied long-term intravenous infusions.

What the reader will gain: While most studies on intravenous ketamine show acute analgesic effects, three recent trials on long-term ketamine treatment (days to weeks) demonstrate the effectiveness of ketamine in causing long-term (months) relief of chronic pain. Despite these positive results, further studies are needed on safety/toxicity issues. Other administration modes are less effective in causing long-term pain relief.

Take home message: There is now evidence form a limited number of studies that pain relief lasting for months is observed after long-term intravenous ketamine infusion, suggesting a modulatory effect of ketamine in the process of chronic pain, possibly via blockade of upregulated NMDAR.     

Preliminary evidence of cannabinoid effects on brain-derived neurotrophic factor (BDNF) levels in humans

Background  Acute and chronic exposure to cannabinoids has been associated with cognitive deficits, a higher risk for schizophrenia and other drug abuse. However, the precise mechanism underlying such effects is not known. Preclinical studies suggest that cannabinoids modulate brain-derived neurotrophic factor (BDNF). Accordingly, we hypothesized that Δ⁹-tetrahydrocannabinol (Δ⁹-THC), the principal active component of cannabis, would alter BDNF levels in humans. Materials and methods  Healthy control subjects (n = 14) and light users of cannabis (n = 9) received intravenous administration of (0.0286 mg/kg) Δ⁹-THC in a double-blind, fixed order, placebo-controlled, laboratory study. Serum sampled at baseline, after placebo administration, and after Δ⁹-THC administration was assayed for BDNF using ELISA. Results  Δ⁹-THC increased serum BDNF levels in healthy controls but not light users of cannabis. Further, light users of cannabis had lower basal BDNF levels. Δ⁹-THC produced psychotomimetic effects, perceptual alterations, and “high” and spatial memory impairments. Implications  The effects of socially relevant doses of cannabinoids on BDNF suggest a possible mechanism underlying the consequences of exposure to cannabis. This may be of particular importance for the developing brain and also in disorders believed to involve altered neurodevelopment such as schizophrenia. Larger studies to investigate the effects of cannabinoids on BDNF and other neurotrophins are warranted.     

Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials

Effective therapeutic options for patients living with chronic pain are limited. The pain relieving effect of cannabinoids remains unclear. A systematic review of randomized controlled trials (RCTs) examining cannabinoids in the treatment of chronic non-cancer pain was conducted according to the PRISMA statement update on the QUORUM guidelines for reporting systematic reviews that evaluate health care interventions. Cannabinoids studied included smoked cannabis, oromucosal extracts of cannabis based medicine, nabilone, dronabinol and a novel THC analogue. Chronic non-cancer pain conditions included neuropathic pain, fibromyalgia, rheumatoid arthritis, and mixed chronic pain. Overall the quality of trials was excellent. Fifteen of the eighteen trials that met the inclusion criteria demonstrated a significant analgesic effect of cannabinoid as compared with placebo and several reported significant improvements in sleep. There were no serious adverse effects. Adverse effects most commonly reported were generally well tolerated, mild to moderate in severity and led to withdrawal from the studies in only a few cases. Overall there is evidence that cannabinoids are safe and modestly effective in neuropathic pain with preliminary evidence of efficacy in fibromyalgia and rheumatoid arthritis. The context of the need for additional treatments for chronic pain is reviewed. Further large studies of longer duration examining specific cannabinoids in homogeneous populations are required.     

Cannabinoids in the treatment of pain and spasticity in multiple sclerosis

There is a large amount of evidence to support the view that the psychoactive ingredient in cannabis, delta9-tetrahydrocannabinol (delta9-THC), and cannabinoids in general, can reduce muscle spasticity and pain under some circumstances. Cannabinoid (CB1) receptors in the CNS appear to mediate both of these effects and endogenous cannabinoids may fulfil these functions to some extent under normal circumstances. However, in the context of multiple sclerosis (MS), it is still questionable whether cannabinoids are superior to existing, conventional medicationsfor the treatment of spasticity and pain. In the case of spasticity, there are too few controlled clinical trials to draw any reliable conclusion at this stage. In the case of pain, most of the available trials suggest that cannabinoids are not superior to existing treatments; however, few trials have examined chronic pain syndromes that are relevant to MS. Whether or not cannabinoids do have therapeutic potential in the treatment of MS, a further issue will be whether synthetic cannabinoids should be used in preference to cannabis itself. Smoking cannabis is associated with significant risks of lung cancer and other respiratory dysfunction. Furthermore, delta9-THC, as a broad-spectrum cannabinoid receptor agonist, will activate both CB1 and CB2 receptors. Synthetic cannabinoids, which target specific cannabinoid receptor subtypes in specific parts of the CNS, are likely to be of more therapeutic use than delta9-THC itself. If rapid absorption is necessary, such synthetic drugs could be delivered via aerosol formulations.     

Emerging drugs for diabetic peripheral neuropathy and neuropathic pain

Introduction: Diabetic sensorimotor polyneuropathy (DSPN) is a common complication of diabetes.

Areas covered: In this review, the authors discuss the emerging drugs for DSPN, which aim either at improving alleviation of neuropathic pain or addressing the putative mechanisms underlying diabetic neuropathy.

Expert Opinion: Current treatment does not address the sensory deficits and pathogenesis underlying DSPN, so there is an unmet need for treatment options targeting the natural history of the condition. Some of these pathogenetic therapies have demonstrated clinically relevant improvements in neuropathic endpoints in recent randomised controlled trials. Since any effective analgesic monotherapy is known to induce a clinically meaningful response in only some 50% of the patients, there remains a substantial unmet need in patients with neuropathic pain. Advanced knowledge in the neurobiology of neuropathic pain and improved phenotypic profiling have led to a burst of research into novel pharmaceutical approaches. An array of promising molecular entities have reached the clinical stage of development, which should improve our therapeutic armamentarium in the fight against DSPN and neuropathic pain in the foreseeable future.     

Perineural injection of botulinum toxin-A in painful peripheral nerve injury – a case series: pain relief,safety, sensory profile and sample size recommendation

Objectives: Subcutaneous injection of botulinum toxin-A (sBONT-A) is a novel treatment for peripheral neuropathic pain. While its analgesic effects are well documented, this treatment is often not comfortable and fails in patients who show signs of sensory loss but rarely allodynia. There are some case reports about perineural BONT-A injection (pBONT-A) which could be an alternative approach. Here we present a retrospective, open label case series of pBONT-A’s efficacy and safety regarding neurological consequences involving changes in somatosensory profiles of both responders and non-responders.

Methods: Sixty patients (53?±?13years, 77% males) with PNI were treated with pBONT-A after a test injection with a local anesthetic, which prompted distinctive pain relief. Quantitative sensory testing (QST; DFNS protocol) and pain intensity were assessed before and ≥7?days post pBONT-A injection. Definition of response: satisfactory pain reduction of ≥30% NRS (numerical rating scale: 0?=?no pain, 10?=?worst pain) for ≥4?days.

Statistics: Paired t-test, Mann–Whitney U-test, χ² test.

Results: A temporary weak paresis in one case was clinically verified. The QST -parameters remained unchanged, but patients with more frequent hyperalgesia signs reported less analgesia (p?=?.04). The pBONT-A injection prompted pain relief by 24.8% (NRS: 6.0?±?1.7 vs. 4.5?±?2.1; p?<?.0001); 57% (n?=?34) were responders (NRS: 6.0?±?1.6 vs. 3.4?±?1.6, relief of 43.4%; p?<?.0001). Based on these results, we suggest that future parallel design trials on pBONT-A need to include at least 84 patients.

Discussion: Ultrasound-guided pBONT-A injection seems to be a safe treatment leading to a sufficient pain relief for some months without sensory changes. Surprisingly, pBONT-A showed a pronounced analgesic effect also in patients without signs of hyperalgesia.     

Combined oral prolonged-release oxycodone and naloxone in opioid-induced bowel dysfunction: review of efficacy and safety data in the treatment of patients experiencing chronic pain

Importance of the field: Despite proven analgesic efficacy, opioid use is associated with frequently dose-limiting bowel dysfunction that seriously impacts patients' quality of life (QoL). Agents used at present to manage opioid-induced constipation do not address the underlying opioid receptor-mediated cause of bowel dysfunction and are often ineffective. There is, therefore, a significant need for more effective treatment options. The combination of the strong opioid oxycodone and the opioid antagonist naloxone has the potential to prevent opioid-induced bowel dysfunction (OIBD) while maintaining analgesic efficacy.

Objective: To review the safety and efficacy of oral prolonged-release (PR) oxycodone/naloxone in the treatment of patients experiencing chronic pain.

Areas covered in this review: A MEDLINE search was done (January 2002 – July 2009) for available literature for prolonged release oxycodone and naloxone in different patient groups. Results were limited to English-language and clinical trials. Data were also obtained from congress materials.

What knowledge the reader will gain: Unmet needs of opioid pain treatment in terms of OIBD, reduced QoL and low treatment compliance, leading to reduced efficacy. A data overview demonstrates the efficacy and tolerability of PR oxycodone/naloxone in the management of severe chronic pain without the burden of severe gastrointestinal adverse events. The combined formulation of a highly effective opioid and an antagonist that acts locally to reduce gastrointestinal side effects is expected to simplify pain management.

Take home message: The combination of PR oxycodone/naloxone offers the potential of maintaining normal bowel function in patients requiring opioid therapy – it is a strong analgesic that is well tolerated.     

Emerging concepts on the use of ketamine for chronic pain

ABSTRACT

Introduction: The use of ketamine infusions for chronic pain has surged, with utilization exceeding the proliferation of knowledge. A proposed mechanism for the long-term benefit in chronic pain is that ketamine may alter the affective-motivational component of pain.

Areas covered: In this review, we discuss the classification and various dimensions of pain, and explore the effects of ketamine on different pain categories and components. The relationship between ketamine’s action at the NMDA receptor, the development of chronic pain, and the its possible role in preventing the persistence of pain are examined. We also summarize animal models evaluating the antinociceptive effects of ketamine and risk mitigation strategies of ketamine-associated side effects.

Expert opinion: Although ketamine exerts most of its analgesic effects via the NMDA receptor, recent evidence suggests that other receptors such as AMPA, and active metabolites such as nor-ketamine, may also play a role in pain relief and alleviation of depression. Data from clinical studies performed in patients with chronic pain and depression, and the observation that ketamine’s analgesic benefits outlast its effects on quantitative sensory testing, suggest that the enduring effects on chronic pain may be predominantly due ketamine’s ability to modulate the affective-motivational dimension of pain.     

Cyclodextrins: improving the therapeutic response of analgesic drugs: a patent review

Introduction: Cyclodextrins (CDs) are cyclic oligosaccharides that have recently been recognized as useful tools for optimizing the delivery of such problematic drugs. CDs can be found in at least 35 pharmaceutical products, such as anticancer agents, analgesic and anti-inflammatory drugs. Besides, several studies have demonstrated that CD-complexed drugs could provide benefits in solubility, stability and also improve pharmacological response when compared with the drug alone.

Areas covered: The patent search was conducted in the databases WIPO, Espacenet, USPTO, Derwent and INPI, using the keywords cyclodextrin, pain and its related terms (analgesia, hyperalgesia, hypernociception, nociception, antinociception, antinociceptive). We found 442 patents. Criteria such as the complexation of analgesic agents and evidence of improvement of the therapeutic effect were indispensable for the inclusion of the patent. So, 18 patents were selected.

Expert opinion: We noticed that some patents are related to the complexation of opioids, NSAIDs, as well as natural products, in different types of CDs. The use of CDs creates the prospect of developing new therapeutic options for the most effective treatment of painful conditions, allowing a reduction of dosage of analgesic drugs and the occurrence of side effects. Thus, CDs can be an important tool to improve the efficacy and pharmacological profile of analgesic drugs.     

Evaluation of the antihyperalgesic effect of tapentadol in two human evoked pain models – the TapCapMentho pilot trial

Objective: Tapentadol is effective in the treatment of neuropathic and nociceptive pain and in acute and chronic pain conditions; two mechanisms combining opioid µ-receptor agonism and noradrenergic reuptake inhibition underlie its analgesic effect.

Research design and methods: With this single-center, placebo-controlled, double-blind, cross-over pilot-study, we investigated the antihyperalgesic effect of a single oral dose of 100 mg immediate-release tapentadol on thermal and mechanical hyperalgesia in two human models (i.e. 0.6 % topical capsaicin and 40% topical menthol) of evoked neuropathic pain signs in healthy volunteers.

Results: No significant differences regarding experimentally induced heat or cold and mechanical (pinprick) hyperalgesia, as assessed by quantitative sensory testing, could be observed between a single dose of drug and placebo (thermal pain thresholds p>0.4, mechanical pain sensitivity p>0.1). Only few mild side effects of tapentadol were reported.

Conclusions: The discrepancy between pain models using healthy volunteers and drug trials under real acute and chronic pain conditions in patients as well as methodological aspects may have contributed to this result. The impact of these findings questions the general use of pain models as predictors for early decision making during drug development.

The study was registered in ClinicalTrials.gov (NCT01615510).     

Chronic pain management issues in the primary care setting and the utility of long-acting opioids

Importance of the field: Chronic/persistent pain – a highly prevalent condition that places a substantial burden on patients in terms of personal suffering, reduced productivity and health care costs – remains inadequately treated in many patients. The purpose of this review is to provide an overview and evaluate the burden and undertreatment of chronic/persistent pain, considerations for choosing an analgesic and the utility of long-acting opioids.

Areas covered in this review: A PubMed search was conducted to identify randomized, placebo-controlled trials evaluating the efficacy and safety of long-acting opioids in chronic pain conditions. The following search terms were used: long-acting opioids, extended-release opioids, controlled-release opioids, sustained-release opioids, and transdermal opioids. The search was limited to randomized, controlled trials published within the last 10 years (1998 – 2008). Studies meeting the following criteria were excluded from review: those focused on a neuropathic pain condition or specific patient subpopulations (e.g., opioid-experienced patients); those conducted outside the USA; and those evaluating a long-acting opioid that is not on the US market at present.

What the reader will gain: The reader will first develop a better understanding of the individual and societal ramifications of undertreated chronic pain. Then, a critical review of safety and efficacy data from well-controlled randomized studies will help readers understand the choices and variables that should be considered when selecting appropriate treatments for patients with chronic pain.

Take home message: Successful management of chronic/persistent pain should be individually tailored to each patient, taking into account his or her pain intensity and duration, disease state, tolerance of adverse events and risk of medication abuse or diversion. The literature supports the efficacy and safety of a number of long-acting opioids for the treatment of moderate to severe chronic pain, demonstrating sustained improvements in pain intensity and pain-related sleep disturbances with these agents.     

Dose-Related Modulation of Event-Related Potentials to Novel and Target Stimuli by Intravenous Δ9-THC in Humans

Cannabinoids induce a host of perceptual alterations and cognitive deficits in humans. However, the neural correlates of these deficits have remained elusive. The current study examined the acute, dose-related effects of delta-9-tetrahydrocannabinol (Δ⁹-THC) on psychophysiological indices of information processing in humans. Healthy subjects (n=26) completed three test days during which they received intravenous Δ⁹-THC (placebo, 0.015 and 0.03 mg/kg) in a within-subject, double-blind, randomized, cross-over, and counterbalanced design. Psychophysiological data (electroencephalography) were collected before and after drug administration while subjects engaged in an event-related potential (ERP) task known to be a valid index of attention and cognition (a three-stimulus auditory ‘oddball'' P300 task). Δ⁹-THC dose-dependently reduced the amplitude of both the target P300b and the novelty P300a. Δ⁹-THC did not have any effect on the latency of either the P300a or P300b, or on early sensory-evoked ERP components preceding the P300 (the N100). Concomitantly, Δ⁹-THC induced psychotomimetic effects, perceptual alterations, and subjective ‘high'' in a dose-dependent manner. Δ⁹-THC -induced reductions in P3b amplitude correlated with Δ⁹-THC-induced perceptual alterations. Lastly, exploratory analyses examining cannabis use status showed that whereas recent cannabis users had blunted behavioral effects to Δ⁹-THC, there were no dose-related effects of Δ⁹-THC on P300a/b amplitude between cannabis-free and recent cannabis users. Overall, these data suggest that at doses that produce behavioral and subjective effects consistent with the known properties of cannabis, Δ⁹-THC reduced P300a and P300b amplitudes without altering the latency of these ERPs. Cannabinoid agonists may therefore disrupt cortical processes responsible for context updating and the automatic orientation of attention, while leaving processing speed and earlier sensory ERP components intact. Collectively, the findings suggest that CB1R systems modulate top-down and bottom-up processing.     

Interleukin (IL)-1β Receptor Type II (Gene Therapy), IL-1β Gene,Nitric Oxide Synthase (NOS), Cyclo-Oxygenase (COX)-2, Tumour Necrosis Factor (TNF)-α Convertase,IL-17, Superoxide Dismutase (SOD), Differential Display of Novel Genes Expressed in Human Osteoarthritis-Affected Cartilage,Human Arthritis-Affected Cartilage Proteases

Introduction: Neuropathic pain and chronic inflammatory pain are large unmet medical needs. Over the past two decades, numerous ’pain targets’ have been identified for analgesic drug discovery. Despite promising results in rodent pain models, many compounds modulating such targets lacked efficacy in clinical trials. An exception is oral EMA401, a small-molecule angiotensin II type 2 receptor (AT₂R) antagonist.

Areas covered: Herein, angiotensin II/AT₂R signaling-induced hyperexcitability and abnormal sprouting of cultured dorsal root ganglion neurons, together with radioligand binding, pharmacokinetics, analgesic efficacy and mode of action of small-molecule AT₂R antagonists in rodent models of peripheral neuropathic and chronic inflammatory pain, are reviewed. The findings of a successful Phase IIa clinical trial of EMA401 in patients with neuropathic pain are presented in brief.

Expert opinion: The functional importance of angiotensin II/AT₂R signaling has remained enigmatic for decades, and there are no clinically available medications that target the AT₂R. However, on the basis of preclinical findings and recent clinical trial data showing that the peripherally restricted, small-molecule AT₂R antagonist, EMA401, successfully alleviated neuropathic pain in a Phase II clinical trial, the AT₂R is receiving considerable attention as a new therapeutic target with human validation for the relief of peripheral neuropathic and chronic inflammatory pain conditions.     

Cannabis Use is Associated with Lower Odds of Prescription Opioid Analgesic Use Among HIV-Infected Individuals with Chronic Pain

Background: Chronic pain is common in the United States and prescribed opioid analgesics use for noncancer pain has increased dramatically in the past two decades, possibly accounting for the current opioid addiction epidemic. Co-morbid drug use in those prescribed opioid analgesics is common, but there are few data on polysubstance use patterns. Objective: We explored patterns of use of cigarette, alcohol, and illicit drugs in HIV-infected people with chronic pain who were prescribed opioid analgesics. Methods: We conducted a secondary data analysis of screening interviews conducted as part of a parent randomized trial of financial incentives to improve HIV outcomes among drug users. In a convenience sample of people with HIV and chronic pain, we collected self-report data on demographic characteristics; pain; patterns of opioid analgesic use (both prescribed and illicit); cigarette, alcohol, and illicit drug use (including cannabis, heroin, and cocaine) within the past 30 days; and current treatment for drug use and HIV. Results: Almost half of the sample of people with HIV and chronic pain reported current prescribed opioid analgesic use (N = 372, 47.1%). Illicit drug use was common (N = 505, 63.9%), and cannabis was the most commonly used illicit substance (N = 311, 39.4%). In multivariate analyses, only cannabis use was significantly associated with lower odds of prescribed opioid analgesic use (adjusted odds ratio = 0.57; 95% confidence interval: 0.38–0.87). Conclusions/Importance: Our data suggest that new medical cannabis legislation might reduce the need for opioid analgesics for pain management, which could help to address adverse events associated with opioid analgesic use.     

Synergistic affective analgesic interaction between delta-9-tetrahydrocannabinol and morphine

Evidence for an analgesic interaction between delta-9-tetrahydrocannabinol (Delta(9)-THC) and morphine was sought using an experimental pain model applied to normal volunteers. The study incorporated a double blinded, four treatment, four period, four sequence, crossover design. Subjects received Delta(9)-THC 5 mg orally or placebo and 90 min later morphine 0.02 mg/kg intravenously or placebo. Fifteen minutes later subjects rated the pain associated with the application of thermal stimuli to skin using two visual analog scales, one for the sensory and one for the affective aspects of pain. Among sensory responses, neither morphine nor Delta(9)-THC had a significant effect at the doses used, and there was no significant interaction between the two. Among affective responses, although neither morphine nor Delta(9)-THC had a significant effect, there was a positive analgesic interaction between the two (p = 0.012), indicating that the combination had a synergistic affective analgesic effect. The surprisingly limited reported experimental experience in humans does not support a role for Delta(9)-THC as an analgesic or as an adjunct to cannabinoid analgesia, except for our finding of synergy limited to the affective component of pain. Comparison of our results with those of others suggests that extrapolation from experimental pain models to the clinic is not likely to be a straight-forward process. Future studies of Delta(9)-THC or other cannabinoids in combination with opiates should focus upon clinical rather than experimental pain.     

Modulation of acute effects of delta-9-tetrahydrocannabinol on psychotomimetic effects,cognition and brain function by previous cannabis exposure

Cannabis use has been associated with psychosis and cognitive dysfunction. Some evidence suggests that the acute behavioral and neurocognitive effects of the main active ingredient in cannabis, (?)-trans-Δ9-tetrahydrocannabinol (?9-THC), might be modulated by previous cannabis exposure. However, this has not been investigated either using a control group of non-users, or following abstinence in modest cannabis users, who represent the majority of recreational users. Twenty-four healthy men participated in a double-blind, randomized, placebo-controlled, repeated-measures, within-subject, ?9-THC challenge study. Compared to non-users (N=12; <5 lifetime cannabis joints smoked), abstinent modest cannabis users (N=12; 24.5±9 lifetime cannabis joints smoked) showed worse performance and stronger right hemispheric activation during cognitive processing, independent of the acute challenge (all P≤0.047). Acute ?9-THC administration produced transient anxiety and psychotomimetic symptoms (all P≤0.02), the latter being greater in non-users compared to users (P=0.040). Non-users under placebo (control group) activated specific brain areas to perform the tasks, while deactivating others. An opposite pattern was found under acute (?9-THC challenge in non-users) as well as residual (cannabis users under placebo) effect of ?9-THC. Under ?9-THC, cannabis users showed brain activity patterns intermediate between those in non-users under placebo (control group), and non-users under ?9-THC (acute effect) and cannabis users under placebo (residual effect). In non-users, the more severe the ?9-THC-induced psychotomimetic symptoms and cognitive impairments, the more pronounced was the neurophysiological alteration (all P≤0.036). Previous modest cannabis use blunts the acute behavioral and neurophysiological effects of ?9-THC, which are more marked in people who have never used cannabis.     

The effects of cannabinoids on serum cortisol and prolactin in humans

Background  Cannabis is one of the most widely used illicit substances, and there is growing interest in the therapeutic applications of cannabinoids. While known to modulate neuroendocrine function, the precise acute and chronic dose-related effects of cannabinoids in humans are not well-known. Furthermore, the existing literature on the neuroendocrine effects of cannabinoids is limited by small sample sizes (n = 6–22), heterogeneous samples with regard to cannabis exposure (lumping users and nonusers), lack of controlling for chronic cannabis exposure, differing methodologies, and limited dose–response data. Delta-9-tetrahydrocannabinol (Δ-9-THC) was hypothesized to produce dose-related increases in plasma cortisol levels and decreases in plasma prolactin levels. Furthermore, relative to controls, frequent users of cannabis were hypothesized to show altered baseline levels of these hormones and blunted Δ-9-THC-induced changes of these hormones. Materials and methods  Pooled data from a series of laboratory studies with multiple doses of intravenous Δ-9-THC in healthy control subjects (n = 36) and frequent users of cannabis (n = 40) was examined to characterize the acute, chronic, and acute on chronic effects of cannabinoids on plasma cortisol and prolactin levels. Hormone levels were measured before (baseline) and 70 min after administration of each dose of Δ-9-THC. Data were analyzed using linear mixed models with +70 min hormonal levels as the dependant variable and baseline hormonal level as the covariate. Results  At socially relevant doses, Δ-9-THC raised plasma cortisol levels in a dose-dependent manner but frequent users showed blunted increases relative to healthy controls. Frequent users also had lower baseline plasma prolactin levels relative to healthy controls. Conclusions  These group differences may be related to the development of tolerance to the neuroendocrine effects of cannabinoids. Alternatively, these results may reflect inherent differences in neuroendocrine function in frequent users of cannabis and not a consequence of cannabis use.